Specific Correlation Between the Major Chromosome 10Q26 Haplotype Conferring Risk for Age-Related Macular Degeneration and the Expression of HTRA1

Total Page:16

File Type:pdf, Size:1020Kb

Specific Correlation Between the Major Chromosome 10Q26 Haplotype Conferring Risk for Age-Related Macular Degeneration and the Expression of HTRA1 Molecular Vision 2017; 23:318-333 <http://www.molvis.org/molvis/v23/318> © 2017 Molecular Vision Received 5 December 2016 | Accepted 12 June 2017 | Published 14 June 2017 Specific correlation between the major chromosome 10q26 haplotype conferring risk for age-related macular degeneration and the expression of HTRA1 Sha-Mei Liao,1 Wei Zheng,1 Jiang Zhu,2 Casey A. Lewis,1 Omar Delgado,1 Maura A. Crowley,1 Natasha M. Buchanan,1 Bruce D. Jaffee,1 Thaddeus P. Dryja1 1Department of Ophthalmology; NIBR Informatics, Novartis Institutes for Biomedical Research, Cambridge, MA; 2Scientific Data Analysis, NIBR Informatics, Novartis Institutes for Biomedical Research, Cambridge, MA Purpose: A region within chromosome 10q26 has a set of single nucleotide polymorphisms (SNPs) that define a haplo- type that confers high risk for age-related macular degeneration (AMD). We used a bioinformatics approach to search for genes in this region that may be responsible for risk for AMD by assessing levels of gene expression in individuals carrying different haplotypes and by searching for open chromatin regions in the retinal pigment epithelium (RPE) that might include one or more of the SNPs. Methods: We surveyed the PubMed and the 1000 Genomes databases to find all common (minor allele frequency > 0.01) SNPs in 10q26 strongly associated with AMD. We used the HaploReg and LDlink databases to find sets of SNPs with alleles in linkage disequilibrium and used the Genotype-Tissue Expression (GTEx) database to search for correlations between genotypes at individual SNPs and the relative level of expression of the genes. We also accessed Encyclopedia of DNA Elements (ENCODE) to find segments of open chromatin in the region with the AMD-associated SNPs. Predicted transcription factor binding motifs were identified using HOMER, PROMO, and RegulomeDB software programs. Results: There are 34 polymorphisms within a 30-kb region that are in strong linkage disequilibrium (r2>0.8) with the reference SNP rs10490924 previously associated with risk for AMD. The expression of three genes in this region, PLEKHA1, ARMS2, and HTRA1 varies between people who have the low-AMD-risk haplotype compared with those with the high-AMD-risk haplotype. For PLEKHA1, 44 tissues have an expression pattern with the high-AMD-risk haplotype associated with low expression (rs10490924 effect size -0.43, p = 3.8 x 10-5 in ovary). With regard to ARMS2, the varia- tion is most pronounced in testes: homozygotes with the high-AMD-risk haplotype express ARMS2 at lower levels than homozygotes with the low-AMD-risk haplotype; expression in heterozygotes falls in between (rs10490924 effect size -0.79, p = 7.5 x 10-24). For HTRA1, the expression pattern is the opposite; the high-AMD-risk haplotype has higher levels of expression in 27 tissues (rs10490924 effect size 0.40, p = 1.5 × 10−7 in testes). None of the other 22 genes within one megabase of rs10490924, or any gene in the entire genome, have mRNA expression levels that correlate with the high- AMD-risk haplotype. More than 100 other SNPs in the 10q26 region affect the expression of PLEKHA1 and ARMS2 but not that of HTRA1; none of these SNPs affects the risk for AMD according to published genome-wide association studies (GWASs). Two of the AMD-risk SNPs (rs36212732 and rs36212733) affect transcription factor binding sites in proximity to a DNase I hypersensitive region (i.e., a region of open chromatin) in RPE cells. Conclusions: SNPs in chromosome 10q26 that influence the expression of onlyPLEKHA1 or ARMS2 are not associated with risk for AMD, while most SNPs that influence the expression ofHTRA1 are associated with risk for AMD. Two of the AMD-risk SNPs affect transcription factor binding sites that may control expression of one of the linked genes in the RPE. These findings suggest that the variation in the risk for AMD associated with chromosome 10q26 is likely due to variation in HTRA1 expression. Modulating HTRA1 activity might be a potential therapy for AMD. Age-related macular degeneration (AMD) is the leading some AMD-risk SNPs change the coding region of genes, cause of severe vision loss in older individuals. Single nucleo- most reside outside coding regions, suggesting potential tide polymorphisms (SNPs) in at least 34 loci influence the effects in regulating the expression of linked genes [2,3]. A risk for AMD [1], and the mechanisms by which these vari- set of closely linked SNPs on chromosome 10q26 is of special ants influence AMD are still being elucidated. Although interest since this chromosome has more influence on the risk for AMD than any other AMD region [1,4-7]; however, which gene in the region confers the risk remains unclear Correspondence to: Sha-Mei Liao, Department of Ophthalmology, [5,8-10]. Three genes are within 100 kilobase pairs (kb) of the Novartis Institutes for Biomedical Research, 22 Windsor Street, Cambridge, MA 02139, USA; Phone: (617) 871 4004; FAX: (617) SNPs associated with AMD. From the centromeric to telo- 871 5784; email: [email protected] meric ends of this region, the genes are pleckstrin homology Dr. Zheng now at GNS Healthcare, Cambridge, MA domain-containing family A member 1 (PLEKHA1; gene ID: 318 Molecular Vision 2017; 23:318-333 <http://www.molvis.org/molvis/v23/318> © 2017 Molecular Vision TABLE 1. THE 34 POLYMORPHISMS IN LINKAGE DISEQUILIBRIUM THAT FORM AN AMD-ASSOCIATED HAPLOTYPE BLOCK. Chr 10 position r2 LDlink/ D' LDlink/ SNP (GPCh37) REF/ALT Allele HaploReg HaploReg AMD References rs61871744 124,203,787 T/C 0.96/0.94 0.99/0.99 rs59616332 124,208,562 ATAAAC/- 0.96/NA 0.99/NA rs11200630 124,209,684 T/C 0.99/0.98 1/0.99 rs61871745 124,210,369 G/A 0.99/0.98 1/0.99 rs11200632 124,211,536 A/G 0.99/0.99 1/1 rs11200633 124,211,596 C/T 0.99/0.98 1/1 rs61871746 124,212,913 T/C 1/1 1/1 rs61871747 124,213,046 C/T 1/1 1/1 rs370974631 124,213,143 AA/- 0.93/NA 1/NA rs200227426 124,213,671 C/A 0.96/NA 0.99/NA rs201396317 124,213,674 C/A 0.96/NA 0.99/NA rs199637836 124,213,677 C/A 0.96/NA 0.99/NA rs11200634 124,213,680 C/A 0.96/NA 0.99/NA rs75431719 124,213,688 C/A 0.96/NA 0.99/NA 22, 23, 24, 25, 26, 27, 28, 36, rs10490924 124,214,448 G/T Reference SNP Reference SNP and additional 140 refs rs144224550 124,214,600 - /GT 1/NA 1/NA rs36212731 124,214,976 G/T 0.99/1 1/1 rs36212732 124,215,198 A/G 1/1 1/1 rs36212733 124,215,211 T/C 1/1 1/1 rs3750848 124,215,315 T/G 1/1 1/1 29 rs3750847 124,215,421 C/T 1/1 1/1 30 rs3750846 124,215,565 T/C 1/1 1/1 1, 29 rs566108895 124,216,823 G/T 0.91/NA 0.99/NA rs3793917 124,219,275 C/G 0.99/0.98 1/0.99 29, 31, 32, 33 rs3763764 124,220,061 A/G 0.98/0.98 0.99/0.99 17, 18, 19, 20, 21, 22, 23, and rs11200638 124,220,544 G/A 0.98/0.9 0.99/0.97 additional 100 refs rs1049331 124,221,270 C/T 0.97/0.96 0.99/0.99 34, 37 rs2293870 124,221,276 G/C,T NA/0.9 NA/0.95 34, 38, 39 rs2284665 124,226,630 G/T 0.96/0.94 0.99/0.98 35 rs60401382 124,227,624 C/T 0.84/0.82 0.98/0.97 rs11200643 124,229,203 C/T 0.82/0.8 0.96/0.94 rs58077526 124,230,024 A/C 0.91/0.89 0.96/0.95 rs932275 124,231,464 G/A 0.93/0.89 0.97/0.96 29 rs2142308 124,234,037 G/C 0.92/0.89 0.97/0.96 The SNP rs10490924 is the reference SNP used to obtain r2 and D’ values in both the HaploReg and LDlink websites. In the 1000 Genome project European population there are 34 polymorphisms, including rs10490924, in linkage disequilibrium using the inclusion criterion r2 ≥0.8 [11,12]. LDlink r2 refers to the strength of the association of the alleles at the queried SNP with rs10490924. LDlink D’ measures linkage disequilibrium normalized for allele frequency. NA = Not Available. 319 Molecular Vision 2017; 23:318-333 <http://www.molvis.org/molvis/v23/318> © 2017 Molecular Vision Figure 1. Diagram of the chromosome 10q26 region containing the PLEKHA1, ARMS2, and HTRA1 genes, as well as the locations of the SNPs that have been associated with risk for AMD by published GWASs and genetic studies. 59338, OMIM: 607772), age-related maculopathy-2 (ARMS2; 6. The mRNA levels are expressed as rank normalized gene gene ID: 387715, OMIM: 611313), and high temperature expression [15]. The effect size of an eQTL is the change in requirement protein A1 (HTRA1; gene ID: 5654, OMIM: the value of the standardized gene expression level with each 602194). It is even conceivable that a more distant gene actu- extra copy of the alternative (ALT) allele relative to the refer- ally confers the risk for AMD. ence allele, conditional to all other adjustments (gender, prob- We searched for associations between AMD-risk SNPs abilistic estimation of expression residuals factors, genotype in the 10q26 region and the expression of closely linked principal components, and genotyping platforms).
Recommended publications
  • The Utility of Genetic Risk Scores in Predicting the Onset of Stroke March 2021 6
    DOT/FAA/AM-21/24 Office of Aerospace Medicine Washington, DC 20591 The Utility of Genetic Risk Scores in Predicting the Onset of Stroke Diana Judith Monroy Rios, M.D1 and Scott J. Nicholson, Ph.D.2 1. KR 30 # 45-03 University Campus, Building 471, 5th Floor, Office 510 Bogotá D.C. Colombia 2. FAA Civil Aerospace Medical Institute, 6500 S. MacArthur Blvd Rm. 354, Oklahoma City, OK 73125 March 2021 NOTICE This document is disseminated under the sponsorship of the U.S. Department of Transportation in the interest of information exchange. The United States Government assumes no liability for the contents thereof. _________________ This publication and all Office of Aerospace Medicine technical reports are available in full-text from the Civil Aerospace Medical Institute’s publications Web site: (www.faa.gov/go/oamtechreports) Technical Report Documentation Page 1. Report No. 2. Government Accession No. 3. Recipient's Catalog No. DOT/FAA/AM-21/24 4. Title and Subtitle 5. Report Date March 2021 The Utility of Genetic Risk Scores in Predicting the Onset of Stroke 6. Performing Organization Code 7. Author(s) 8. Performing Organization Report No. Diana Judith Monroy Rios M.D1, and Scott J. Nicholson, Ph.D.2 9. Performing Organization Name and Address 10. Work Unit No. (TRAIS) 1 KR 30 # 45-03 University Campus, Building 471, 5th Floor, Office 510, Bogotá D.C. Colombia 11. Contract or Grant No. 2 FAA Civil Aerospace Medical Institute, 6500 S. MacArthur Blvd Rm. 354, Oklahoma City, OK 73125 12. Sponsoring Agency name and Address 13. Type of Report and Period Covered Office of Aerospace Medicine Federal Aviation Administration 800 Independence Ave., S.W.
    [Show full text]
  • Genetic Variant in 3' Untranslated Region of the Mouse Pycard Gene
    bioRxiv preprint doi: https://doi.org/10.1101/2021.03.26.437184; this version posted March 26, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 2 3 Title: 4 Genetic Variant in 3’ Untranslated Region of the Mouse Pycard Gene Regulates Inflammasome 5 Activity 6 Running Title: 7 3’UTR SNP in Pycard regulates inflammasome activity 8 Authors: 9 Brian Ritchey1*, Qimin Hai1*, Juying Han1, John Barnard2, Jonathan D. Smith1,3 10 1Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, 11 Cleveland, OH 44195 12 2Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 13 44195 14 3Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western 15 Reserve University, Cleveland, OH 44195 16 *, These authors contributed equally to this study. 17 Address correspondence to Jonathan D. Smith: email [email protected]; ORCID ID 0000-0002-0415-386X; 18 mailing address: Cleveland Clinic, Box NC-10, 9500 Euclid Avenue, Cleveland, OH 44195, USA. 19 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.03.26.437184; this version posted March 26, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 20 Abstract 21 Quantitative trait locus mapping for interleukin-1 release after inflammasome priming and activation 22 was performed on bone marrow-derived macrophages (BMDM) from an AKRxDBA/2 strain intercross.
    [Show full text]
  • Gene Interaction of CFH, ARMS2, and ARMS2&Sol;HTRA1 on the Risk Of
    Eye (2015) 29, 691–698 © 2015 Macmillan Publishers Limited All rights reserved 0950-222X/15 www.nature.com/eye 1,2,3,5 1,2,3,5 4,5 Gene–gene interaction L Huang , Q Meng , C Zhang , LABORATORY STUDY Y Sun1,2,3, Y Bai1,2,3,SLi1,2,3, X Deng1,2,3, of CFH, ARMS2, and B Wang1,2,3,WYu1,2,3, M Zhao1,2,3 and X Li1,2,3 ARMS2/HTRA1 on the risk of neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in Chinese population Abstract rs1065489 did not show significant association with nAMD (P40.01), but was strongly Purpose To evaluate the association and associated with PCV in Chinese patients 1Department of interaction of five single-nucleotide (Po0.001). Ophthalmology, Peking polymorphisms (SNPs) in three genes (CFH, University People’s Conclusions In this study, we found that the ARMS2, and ARMS2/HTRA1) with Hospital, Beijing, China interaction of ARMS2 and ARMS2/HTRA1 is neovascular age-related macular degeneration significantly associated with nAMD, and the 2 (nAMD) and polypoidal choroidal Key Laboratory of Vision interaction of CFH and ARMS2 is pronounced vasculopathy (PCV) in Chinese population. Loss and Restoration, in PCV development in Chinese population. Ministry of Education, Methods A total of 300 nAMD and 300 PCV Eye 29, – Beijing, China patients and 301 normal subjects participated (2015) 691 698; doi:10.1038/eye.2015.32; published online 13 March 2015 in the present study. The allelic variants of 3Department of Abdominal rs800292, rs2274700, rs3750847, rs3793917, and Surgical Oncology, Cancer rs1065489 were determined by matrix-assisted Institute and Hospital, Introduction laser desorption/ionization time-of-flight mass Chinese Academy of Medical Sciences, Peking – Age-related macular degeneration (AMD) is the spectrometry (MALDI-TOF-MS).
    [Show full text]
  • Genetic Susceptibility to Age-Related Macular Degeneration: a Paradigm for Dissecting Complex Disease Traits
    Human Molecular Genetics, 2007, Vol. 16, Review Issue 2 R174–R182 doi:10.1093/hmg/ddm212 Genetic susceptibility to age-related macular degeneration: a paradigm for dissecting complex disease traits Anand Swaroop1,2,*, Kari EH Branham1, Wei Chen3 and Goncalo Abecasis3,* 1Departments of Ophthalmology and Visual Sciences, 2Department of Human Genetics and 3Department of Biostatistics, University of Michigan, Ann Arbor, MI 48105, USA Received July 20, 2007; Revised July 20, 2007; Accepted July 26, 2007 Age-related macular degeneration (AMD) is a progressive neurodegenerative disease, which affects quality of life for millions of elderly individuals worldwide. AMD is associated with a diverse spectrum of clinical phe- notypes, all of which include the death of photoreceptors in the central part of the human retina (called the macula). Tremendous progress has been made in identifying genetic susceptibility variants for AMD. Variants at chromosome 1q32 (in the region of CFH ) and 10q26 (LOC387715/ARMS2) account for a large part of the genetic risk to AMD and have been validated in numerous studies. In addition, susceptibility var- iants at other loci, several as yet unidentified, make substantial cumulative contribution to genetic risk for AMD; among these, multiple studies support the role of variants in APOE and C2/BF genes. Genome-wide association and re-sequencing projects, together with gene-environment interaction studies, are expected to further define the causal relationships that connect genetic variants to AMD pathogenesis and should assist in better design of prevention and intervention. INTRODUCTION studies of AMD illustrate both the promise and challenges of new gene-mapping approaches. Early-onset maculopathies, A vast majority of common diseases are complex and such as Stargardt’s disease, have long been known to have her- multi-factorial, resulting from the interplay of genetic com- editary basis.
    [Show full text]
  • Anti-PLEKHA1 / TAPP1 Antibody (ARG42988)
    Product datasheet [email protected] ARG42988 Package: 100 μl anti-PLEKHA1 / TAPP1 antibody Store at: -20°C Summary Product Description Rabbit Polyclonal antibody recognizes PLEKHA1 / TAPP1 Tested Reactivity Hu, Ms, Rat Tested Application IP, WB Host Rabbit Clonality Polyclonal Isotype IgG Target Name PLEKHA1 / TAPP1 Antigen Species Human Immunogen Synthetic peptide of Human PLEKHA1 / TAPP1. Conjugation Un-conjugated Alternate Names Pleckstrin homology domain-containing family A member 1; TAPP1; Tandem PH domain-containing protein 1; TAPP-1; PH domain-containing family A member 1 Application Instructions Application table Application Dilution IP 1:20 WB 1:1000 Application Note * The dilutions indicate recommended starting dilutions and the optimal dilutions or concentrations should be determined by the scientist. Positive Control K562 Calculated Mw 46 kDa Observed Size ~ 46 kDa Properties Form Liquid Purification Affinity purified. Buffer 50 nM Tris-Glycine (pH 7.4), 0.15M NaCl, 0.01% Sodium azide, 40% Glycerol and 0.05% BSA. Preservative 0.01% Sodium azide Stabilizer 40% Glycerol and 0.05% BSA Storage instruction For continuous use, store undiluted antibody at 2-8°C for up to a week. For long-term storage, aliquot and store at -20°C. Storage in frost free freezers is not recommended. Avoid repeated freeze/thaw cycles. Suggest spin the vial prior to opening. The antibody solution should be gently mixed before use. www.arigobio.com 1/2 Note For laboratory research only, not for drug, diagnostic or other use. Bioinformation Gene Symbol PLEKHA1 Gene Full Name pleckstrin homology domain containing, family A (phosphoinositide binding specific) member 1 Background This gene encodes a pleckstrin homology domain-containing adapter protein.
    [Show full text]
  • Transcriptome Analysis of Human Diabetic Kidney Disease
    ORIGINAL ARTICLE Transcriptome Analysis of Human Diabetic Kidney Disease Karolina I. Woroniecka,1 Ae Seo Deok Park,1 Davoud Mohtat,2 David B. Thomas,3 James M. Pullman,4 and Katalin Susztak1,5 OBJECTIVE—Diabetic kidney disease (DKD) is the single cases, mild and then moderate mesangial expansion can be leading cause of kidney failure in the U.S., for which a cure has observed. In general, diabetic kidney disease (DKD) is not yet been found. The aim of our study was to provide an considered a nonimmune-mediated degenerative disease unbiased catalog of gene-expression changes in human diabetic of the glomerulus; however, it has long been noted that kidney biopsy samples. complement and immunoglobulins sometimes can be de- — tected in diseased glomeruli, although their role and sig- RESEARCH DESIGN AND METHODS Affymetrix expression fi arrays were used to identify differentially regulated transcripts in ni cance is not clear (4). 44 microdissected human kidney samples. The DKD samples were The understanding of DKD has been challenged by multi- significant for their racial diversity and decreased glomerular ple issues. First, the diagnosis of DKD usually is made using filtration rate (~20–30 mL/min). Stringent statistical analysis, using clinical criteria, and kidney biopsy often is not performed. the Benjamini-Hochberg corrected two-tailed t test, was used to According to current clinical practice, the development of identify differentially expressed transcripts in control and diseased albuminuria in patients with diabetes is sufficient to make the glomeruli and tubuli. Two different Web-based algorithms were fi diagnosis of DKD (5). We do not understand the correlation used to de ne differentially regulated pathways.
    [Show full text]
  • Nuclear PTEN Safeguards Pre-Mrna Splicing to Link Golgi Apparatus for Its Tumor Suppressive Role
    ARTICLE DOI: 10.1038/s41467-018-04760-1 OPEN Nuclear PTEN safeguards pre-mRNA splicing to link Golgi apparatus for its tumor suppressive role Shao-Ming Shen1, Yan Ji2, Cheng Zhang1, Shuang-Shu Dong2, Shuo Yang1, Zhong Xiong1, Meng-Kai Ge1, Yun Yu1, Li Xia1, Meng Guo1, Jin-Ke Cheng3, Jun-Ling Liu1,3, Jian-Xiu Yu1,3 & Guo-Qiang Chen1 Dysregulation of pre-mRNA alternative splicing (AS) is closely associated with cancers. However, the relationships between the AS and classic oncogenes/tumor suppressors are 1234567890():,; largely unknown. Here we show that the deletion of tumor suppressor PTEN alters pre-mRNA splicing in a phosphatase-independent manner, and identify 262 PTEN-regulated AS events in 293T cells by RNA sequencing, which are associated with significant worse outcome of cancer patients. Based on these findings, we report that nuclear PTEN interacts with the splicing machinery, spliceosome, to regulate its assembly and pre-mRNA splicing. We also identify a new exon 2b in GOLGA2 transcript and the exon exclusion contributes to PTEN knockdown-induced tumorigenesis by promoting dramatic Golgi extension and secretion, and PTEN depletion significantly sensitizes cancer cells to secretion inhibitors brefeldin A and golgicide A. Our results suggest that Golgi secretion inhibitors alone or in combination with PI3K/Akt kinase inhibitors may be therapeutically useful for PTEN-deficient cancers. 1 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine (SJTU-SM), Shanghai 200025, China. 2 Institute of Health Sciences, Shanghai Institutes for Biological Sciences of Chinese Academy of Sciences and SJTU-SM, Shanghai 200025, China.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 7,972,787 B2 Deangelis (45) Date of Patent: Jul
    US007972 787B2 (12) United States Patent (10) Patent No.: US 7,972,787 B2 Deangelis (45) Date of Patent: Jul. 5, 2011 (54) METHODS FOR DETECTINGAGE-RELATED WO WO-2006088950 8, 2006 MACULAR DEGENERATION WO WO-2006133295 A2 12/2006 WO WO-2007044897 A1 4/2007 WO WO-2008O13893 A2 1, 2008 (75) Inventor: Margaret M. Deangelis, Cambridge, WO WO-2008067551 A2 6, 2008 MA (US) WO WO-2008094,370 A2 8, 2008 WO WO-2008103299 A2 8, 2008 WO WO-2008110828 A1 9, 2008 (73) Assignee: Massachusetts Eye and Ear Infirmary, WO WO-2008103299 A3 12/2008 Boston, MA (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this Hirschhornet al. Genetics in Medicine. Mar. 2002. vol. 4. No. 2, pp. patent is extended or adjusted under 35 45-61 U.S.C. 154(b) by 391 days. Yang et all. Science. 2006. 314: 992-993 and supplemental online content. (21) Appl. No.: 12/032,154 GeneCard for the HTRA1 gene available via url: <genecards.org/cgi bin/carddisp.pl?gene=Htral D, printed Jul. 20, 2010.* Lucentini et al. The Scientist (2004) vol. 18, p. 20.* (22) Filed: Feb. 15, 2008 Wacholder et al. J. Natl. Cancer Institute (2004) 96(6);434-442.* Ioannidis et al. Nature genetics (2001) 29:306-309.* (65) Prior Publication Data Halushka et al. Nature. Ju1 1999. 22: 239-247. “HtrA1: A novel TGFB antagonist.” Development (2003) 131:502. US 2008/O2O6263 A1 Aug. 28, 2008 Adams et al. “HTRA1 Genotypes Associated with Risk of Neovascular Age-related Macular Degeneration Independent of CFH Related U.S.
    [Show full text]
  • Population-Haplotype Models for Mapping and Tagging Structural Variation Using Whole Genome Sequencing
    Population-haplotype models for mapping and tagging structural variation using whole genome sequencing Eleni Loizidou Submitted in part fulfilment of the requirements for the degree of Doctor of Philosophy Section of Genomics of Common Disease Department of Medicine Imperial College London, 2018 1 Declaration of originality I hereby declare that the thesis submitted for a Doctor of Philosophy degree is based on my own work. Proper referencing is given to the organisations/cohorts I collaborated with during the project. 2 Copyright Declaration The copyright of this thesis rests with the author and is made available under a Creative Commons Attribution Non-Commercial No Derivatives licence. Researchers are free to copy, distribute or transmit the thesis on the condition that they attribute it, that they do not use it for commercial purposes and that they do not alter, transform or build upon it. For any reuse or redistribution, researchers must make clear to others the licence terms of this work 3 Abstract The scientific interest in copy number variation (CNV) is rapidly increasing, mainly due to the evidence of phenotypic effects and its contribution to disease susceptibility. Single nucleotide polymorphisms (SNPs) which are abundant in the human genome have been widely investigated in genome-wide association studies (GWAS). Despite the notable genomic effects both CNVs and SNPs have, the correlation between them has been relatively understudied. In the past decade, next generation sequencing (NGS) has been the leading high-throughput technology for investigating CNVs and offers mapping at a high-quality resolution. We created a map of NGS-defined CNVs tagged by SNPs using the 1000 Genomes Project phase 3 (1000G) sequencing data to examine patterns between the two types of variation in protein-coding genes.
    [Show full text]
  • A Multiethnic Genome-Wide Analysis of 44,039 Individuals Identifies 41 New Loci Associated with Central Corneal Thickness
    ARTICLE https://doi.org/10.1038/s42003-020-1037-7 OPEN A multiethnic genome-wide analysis of 44,039 individuals identifies 41 new loci associated with central corneal thickness ✉ Hélène Choquet 1 , Ronald B. Melles2, Jie Yin1, Thomas J. Hoffmann 3,4, Khanh K. Thai1, Mark N. Kvale3, 1234567890():,; Yambazi Banda3, Alison J. Hardcastle 5,6, Stephen J. Tuft7, M. Maria Glymour4, Catherine Schaefer 1, ✉ Neil Risch1,3,4, K. Saidas Nair8, Pirro G. Hysi 9,10,11 & Eric Jorgenson 1 Central corneal thickness (CCT) is one of the most heritable human traits, with broad-sense heritability estimates ranging between 0.68 to 0.95. Despite the high heritability and numerous previous association studies, only 8.5% of CCT variance is currently explained. Here, we report the results of a multiethnic meta-analysis of available genome-wide asso- ciation studies in which we find association between CCT and 98 genomic loci, of which 41 are novel. Among these loci, 20 were significantly associated with keratoconus, and one (RAPSN rs3740685) was significantly associated with glaucoma after Bonferroni correction. Two-sample Mendelian randomization analysis suggests that thinner CCT does not causally increase the risk of primary open-angle glaucoma. This large CCT study explains up to 14.2% of CCT variance and increases substantially our understanding of the etiology of CCT var- iation. This may open new avenues of investigation into human ocular traits and their rela- tionship to the risk of vision disorders. 1 Kaiser Permanente Northern California (KPNC), Division of Research, Oakland, CA 94612, USA. 2 KPNC, Department of Ophthalmology, Redwood City, CA 94063, USA.
    [Show full text]
  • Genomic Evidence of Reactive Oxygen Species Elevation in Papillary Thyroid Carcinoma with Hashimoto Thyroiditis
    Endocrine Journal 2015, 62 (10), 857-877 Original Genomic evidence of reactive oxygen species elevation in papillary thyroid carcinoma with Hashimoto thyroiditis Jin Wook Yi1), 2), Ji Yeon Park1), Ji-Youn Sung1), 3), Sang Hyuk Kwak1), 4), Jihan Yu1), 5), Ji Hyun Chang1), 6), Jo-Heon Kim1), 7), Sang Yun Ha1), 8), Eun Kyung Paik1), 9), Woo Seung Lee1), Su-Jin Kim2), Kyu Eun Lee2)* and Ju Han Kim1)* 1) Division of Biomedical Informatics, Seoul National University College of Medicine, Seoul, Korea 2) Department of Surgery, Seoul National University Hospital and College of Medicine, Seoul, Korea 3) Department of Pathology, Kyung Hee University Hospital, Kyung Hee University School of Medicine, Seoul, Korea 4) Kwak Clinic, Okcheon-gun, Chungbuk, Korea 5) Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, Uijeongbu, Korea 6) Department of Radiation Oncology, Seoul St. Mary’s Hospital, Seoul, Korea 7) Department of Pathology, Chonnam National University Hospital, Kwang-Ju, Korea 8) Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 9) Department of Radiation Oncology, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea Abstract. Elevated levels of reactive oxygen species (ROS) have been proposed as a risk factor for the development of papillary thyroid carcinoma (PTC) in patients with Hashimoto thyroiditis (HT). However, it has yet to be proven that the total levels of ROS are sufficiently increased to contribute to carcinogenesis. We hypothesized that if the ROS levels were increased in HT, ROS-related genes would also be differently expressed in PTC with HT. To find differentially expressed genes (DEGs) we analyzed data from the Cancer Genomic Atlas, gene expression data from RNA sequencing: 33 from normal thyroid tissue, 232 from PTC without HT, and 60 from PTC with HT.
    [Show full text]
  • 1 Fibrillar Αβ Triggers Microglial Proteome Alterations and Dysfunction in Alzheimer Mouse 1 Models 2 3 4 Laura Sebastian
    bioRxiv preprint doi: https://doi.org/10.1101/861146; this version posted December 2, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. 1 Fibrillar triggers microglial proteome alterations and dysfunction in Alzheimer mouse 2 models 3 4 5 Laura Sebastian Monasor1,10*, Stephan A. Müller1*, Alessio Colombo1, Jasmin König1,2, Stefan 6 Roth3, Arthur Liesz3,4, Anna Berghofer5, Takashi Saito6,7, Takaomi C. Saido6, Jochen Herms1,4,8, 7 Michael Willem9, Christian Haass1,4,9, Stefan F. Lichtenthaler 1,4,5# & Sabina Tahirovic1# 8 9 1 German Center for Neurodegenerative Diseases (DZNE) Munich, 81377 Munich, Germany 10 2 Faculty of Chemistry, Technical University of Munich, Garching, Germany 11 3 Institute for Stroke and Dementia Research (ISD), Ludwig-Maximilians Universität München, 12 81377 Munich, Germany 13 4 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany 14 5 Neuroproteomics, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, 15 Munich, Germany 16 6 Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science Institute, Wako, 17 Saitama 351-0198, Japan 18 7 Department of Neurocognitive Science, Nagoya City University Graduate School of Medical 19 Science, Nagoya, Aichi 467-8601, Japan 20 8 Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität München, 81377 21 Munich, Germany 22 9 Biomedical Center (BMC), Ludwig-Maximilians Universität München, 81377 Munich, Germany 23 10 Graduate School of Systemic Neuroscience, Ludwig-Maximilians-University Munich, Munich, 24 Germany. 25 *Contributed equally 26 #Correspondence: [email protected] and [email protected] 27 28 Running title: 29 Microglial proteomic signatures of AD 30 Keywords: Alzheimer’s disease / microglia / proteomic signatures / neuroinflammation / 31 phagocytosis 32 1 bioRxiv preprint doi: https://doi.org/10.1101/861146; this version posted December 2, 2019.
    [Show full text]